Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines

Abstract

SummaryThe relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled (Fidler, 1990). Basement membrane degradation (BMD) is brought about by extracellular proteinases, and there is currently interest in inhibitors of these enzymes as potential therapeutic agents. Possible candidates for the proteinases involved in breast cancer invasion are found in each of the four major classes of proteinases, i.e. aspartic, cysteine, serine and matrix metalloproteinases (MMPs).The aspartic proteinase cathepsin D, a lysosomal enzyme, is oversecreted by breast cancer cells in vitro and may be a major proteinase involved in BMD (Briozzo et al, 1988). This view is supported by in vivo experiments in which transfection of cathepsin D cDNA resulted in a higher frequency of metastases in mice (Garcia et al, 1990). Nevertheless, some workers have questioned whether this lysosomal enzyme, which is only active at acid pH, has a role in invasion under physiological conditions (Johnson et al, 1993).The cysteine proteinases, cathepsins B, L and H, are also lysosomal enzymes that are overexpressed in breast cancer (Vasishta et al, 1988;Gabrijelcic et al, 1992). Cathepsin B from normal human liver and from human breast carcinomas has been shown to degrade components of BM at neutral pH as well as at acid pH (Buck et al,

Proteolysis in human breast and colorectal cancer

“…For example, proteinase inhibitors have been used to try and inhibit angiogenesis in an attempt to prevent and slow down tumour progression (Taraboletti et al, 1995;Conway et al, 1996;Stonelake et al, 1997;Yu et al, 1997). A better understanding of the proteinases and inhibitors involved in tumour progression may allow for therapeutic intervention at the earlier stages of tumour progression.…”

Increased plasminogen binding is associated with metastatic breast cancer cells: differential expression of plasminogen binding proteins

“…It is therefore difficult to design specific experiments aimed at establishing a direct relationship between plasminogen binding capacity and metastatic potential without identifying all of the plasminogen binding moieties on the breast cancer cell lines. However, Stonelake et al (1997) recently demonstrated that, in the presence of plasminogen, MDA-MB-231 and other metastatic breast cancer cell lines, unlike non-metastatic cell lines, such as MCF-7 and T-47D, had the ability to degrade human endothelial basement membrane and that this activity was significantly inhibited by specific uPA or plasmin inhibitors. These authors also demonstrated a similar inhibitory effect by lysine analogues and attributed this result to an inhibition of plasminogen binding.…”

“…Nevertheless, dissolution of matrix via plasminogen activation at the cell surface is important for metastasis to occur. Indeed, the inhibition of uPA and plasmin by specific inhibitors or antibodies, or antisense inhibition of uPAR resulted in decreased plasminogen activation and hence decreased extracellular matrix degradation in vitro or decreased metastasis in nude mouse models with various cancer cell lines (Baker et al, 1990;Kook et al, 1994), including human breast cancer cell lines (HolstHansen et al, 1996;Stonelake et al, 1997). In vitro invasiveness has been correlated with uPA and plasmin activity as well as high uPAR and plasminogen activator inhibitor type 1 (PAI-1) protein levels in human breast cancer cell lines (Holst-Hansen et al, 1996).…”

The topology of plasminogen binding and activation on the surface of human breast cancer cells

“…The metastatic human breast cancer cell line MDA-MB-231 has a high glu-plasminogen binding capacity and cell surface uPA antigen levels (Ranson et al, 1998). This results in the generation of significant amounts of cell-surfaceassociated plasmin (Ranson et al, 1998) which facilitates the degradation of human endothelial basement membranes (Stonelake et al, 1997).…”